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EP3966205A1 - In der behandlung einer hbv-infektion oder von hbv-induzierten erkrankungen nützliche amidderivate - Google Patents

In der behandlung einer hbv-infektion oder von hbv-induzierten erkrankungen nützliche amidderivate

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Publication number
EP3966205A1
EP3966205A1 EP20725652.0A EP20725652A EP3966205A1 EP 3966205 A1 EP3966205 A1 EP 3966205A1 EP 20725652 A EP20725652 A EP 20725652A EP 3966205 A1 EP3966205 A1 EP 3966205A1
Authority
EP
European Patent Office
Prior art keywords
compound
group
hbv
alkyl
mmol
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP20725652.0A
Other languages
English (en)
French (fr)
Inventor
Bart Rudolf Romanie Kesteleyn
Jan Martin BERKE
Erwin Coesemans
Sandrine Céline GROSSE
Edgar Jacoby
Tim Hugo Maria Jonckers
Stefaan Julien Last
Wim Gaston Verschueren
Michel OBRINGER
Christelle Catherine Cecile DOEBELIN
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Janssen Sciences Ireland ULC
Original Assignee
Janssen Sciences Ireland ULC
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Janssen Sciences Ireland ULC filed Critical Janssen Sciences Ireland ULC
Publication of EP3966205A1 publication Critical patent/EP3966205A1/de
Withdrawn legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4192—1,2,3-Triazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/20—Antivirals for DNA viruses
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings

Definitions

  • the application relates to amide derivatives, processes for their preparation, pharmaceutical compositions, and their uses, more particularly their uses in treating chronic hepatitis B virus (HBV) infection or HBV-induced diseases.
  • HBV chronic hepatitis B virus
  • HBV infection chronic hepatitis B virus (HBV) infection is a significant global health problem, affecting over 5% of the world population (over 350 million people worldwide and 1.25 million individuals in the U.S.).
  • HBV human immunodeficiency virus
  • Current treatments do not provide a cure and are limited to only two classes of agents (interferon alpha and nucleoside analogues/inhibitors of the viral polymerase); drug resistance, low efficacy, and tolerability issues limit their impact.
  • the low cure rates of HBV are attributed at least in part to the fact that complete suppression of virus production is difficult to achieve with a single antiviral agent.
  • persistent suppression of HBV DNA slows liver disease progression and helps to prevent hepatocellular carcinoma.
  • Current therapy goals for HBV-infected patients are directed to reducing serum HBV DNA to low or undetectable levels, and to ultimately reducing or preventing the development of cirrhosis and hepatocellular carcinoma.
  • HBV capsid protein plays essential functions during the viral life cycle.
  • HBV capsid/core proteins form metastable viral particles or protein shells that protect the viral genome during intercellular passage, and also play a central role in viral replication processes, including genome encapsidation, genome replication, and virion morphogenesis and egress.
  • Capsid structures also respond to environmental cues to allow un-coating after viral entry.
  • WO2015/059212 discloses amide derivatives for the treatment of hepatitis B.
  • the present invention is directed to compounds capable of capsid assembly modulation.
  • the compounds of the present invention may provide a beneficial balance of properties with respect to prior art compounds.
  • a compound of formula (I) is provided herein.
  • stereoisomers or tautomeric forms thereof including the stereoisomers or tautomeric forms thereof, wherein: represents a 6-membered aryl ring optionally containing one or more heteroatom(s), the heteroatom or each of the heteroatoms being nitrogen;
  • R 1 , R 2 and R 3 are each independently selected from the group consisting of H, F, Cl, Br, CHF 2 , CH 2 F, CF 3 , CN, Ci- 4 alkyl and C 3-6 cycloalkyl;
  • R 4 is selected from the group consisting of H and F;
  • R 5a and R 5b are each independently selected from the group consisting of H, Ci- 4 alkyl optionally substituted with one or more F, and C 3-6 cycloalkyl optionally substituted with one or more F;
  • R 6a and R 6b are each independently selected from the group consisting of H, Ci- 4 alkyl optionally substituted with one or more F, and C 3-6 cycloalkyl optionally substituted with one or more F;
  • R 7a and R 7b are each independently selected from the group consisting of H, Ci- 4 alkyl optionally substituted with one or more F, and C 3-6 cycloalkyl optionally substituted with one or more F;
  • Q is selected from the group consisting of
  • Ci-salkyl optionally substituted with one or more substituents selected from the group consisting of halogens;
  • the (3- to 6-membered monocyclic or up to 9-membered polycyclic) saturated rings - optionally and independently contain one or more heteroatoms, the heteroatoms being independently selected from N, O and S, and/or
  • R 8 is H
  • R 9 is selected from the group consisting of
  • heteroatoms containing one to 4 heteroatoms, the heteroatoms being each independently selected from N, O and S, and
  • heteroatoms being each independently selected from N, O and S, substituted with one or more substituents selected from the group consisting of halogens, CN, CF 3 , CF 2 H, CH 2 F, Ci- 4 alkyl, C 3 - 6cycloalkyl, OH and OCi- 4 alkyl;
  • the application provides a pharmaceutical composition
  • a pharmaceutical composition comprising at least one compound of formula (I), or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier.
  • the application provides a pharmaceutical composition comprising at least one disclosed compound, together with a pharmaceutically acceptable carrier.
  • a method of treating an HBV infection in an individual in need thereof comprising administering to the individual a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof or of a pharmaceutical composition as described herein.
  • the application provides a product comprising a first compound and a second compound as a combined preparation for simultaneous, separate or sequential use in the prevention or treatment of an HBV infection or of an HBV-induced disease in mammal in need thereof, wherein said first compound is different from said second compound, wherein said first compound is a compound of formula (I), or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition described in the foregoing paragraph, and wherein said second compound is an HBV inhibitor.
  • the application provides a method of inhibiting or reducing the formation or presence of HBV DNA-containing particles or HBV RNA-containing particles in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof.
  • Any of the methods provided herein can further comprise administering to the individual at least one additional therapeutic agent, more particularly at least one other HBV inhibitor.
  • compounds e.g., the compounds of formula (I), or pharmaceutically acceptable salts thereof, which are notably useful in the treatment or prevention of HBV infection or of an HBV-associated (or HBV-induced) condition or disease in a subject in need thereof.
  • these compounds are believed to modulate or disrupt HBV capsid assembly and other HBV core protein (HBc) functions necessary for HBV replication or the generation of infectious particles and/or may disrupt HBV capsid assembly leading to empty capsids with greatly reduced infectivity or replication capacity.
  • the compounds provided herein may act as Capsid Assembly Modulators or core protein allosteric modulators (CpAMs).
  • the compounds provided herein have potent antiviral activity, and are believed to exhibit favorable metabolic properties, tissue distribution, safety and pharmaceutical profiles, and to be suitable for use in humans.
  • Disclosed compounds may modulate (e.g., accelerate, delay, inhibit, disrupt or reduce) normal viral capsid assembly or disassembly, bind capsid or alter metabolism of cellular polyproteins and precursors. The modulation may occur when the capsid protein is mature, or during viral infectivity.
  • Disclosed compounds can be used in methods of modulating the activity or properties of HBV cccDNA, or the generation or release of HBV RNA particles from within an infected cell.
  • a compound of the application may accelerate the kinetics of HBV capsid assembly, thereby preventing or competing with the encapsidation of the Pol-pgRNA complex and thus blocking the reverse transcription of the pgRNA.
  • a compound of the application can be assessed e.g., by evaluating the capacity of the compound to induce or to not induce speckling of the Hepatitis B virus core protein (HBc).
  • HBc Hepatitis B virus core protein
  • HBc is a small protein of about 21kDa, which forms the icosahedral capsid. HBc has been described e.g., in Diab et al. 2018 (Antiviral Research 149 (2016) 211-220).
  • Capsid assembly modulators may induce the formation of morphologically intact capsids or the formation of pleiomorphic non-capsid structures.
  • Pleiomorphic non-capsid structures can be visualized in stable HBV-replicating cell lines by immunofluorescence staining against the HBV core protein and appear as "core speckling" in the nucleus and cytoplasm.
  • HBc speckling thus refers to the capacity of inducing the formation of such pleiomorphic noncapsid structures.
  • the application relates more particularly to a compound (as herein described), which does not induce speckling of HBc.
  • the application relates more particularly to a compound (as herein described), which induces speckling of HBc.
  • the capacity to induce or to not induce HBc speckling can be assessed by any means which the person of ordinary skill in the art finds appropriate, e.g., by:
  • HBV-infected cells e.g., cells from a (stable) HBV-infected cell line or HBV infected cells which have been previously collected from an HBV patient
  • HBV-infected cells e.g., cells from a (stable) HBV-infected cell line or HBV infected cells which have been previously collected from an HBV patient
  • Determining whether contacting of these cells with the compound of the application induces or does not induce HBc speckling can e.g., involve immunofluorescence staining against HBc, more particularly immunofluorescence staining against HBc with an anti-HBc antibody.
  • Examples of method to determine whether a compound of the application has or not the capacity to induce HBc speckling comprise the method described in the examples below, and the immunofluorescence assay described in Corcuera et al. 2018 (Antiviral Research (2016), doi/ 10.1016/j. antiviral.2018.07.011, ‘Wove/ non-heteroarylpyrimidine (HAP) capsid assembly modifiers have a differ ent mode of action from HAPs in vitro”; cf. ⁇ 2.8 of Corcuera et al. 2018).
  • Figure 5 of Corcuera et al. 2018 illustrates HBV core morphology when a test compound induces HBc speckling (cf.
  • the compounds described herein are suitable for monotherapy and are effective against natural or native HBV strains and against HBV strains resistant to currently known drugs. In another embodiment, the compounds described herein are suitable for use in combination therapy.
  • the articles“a” and“an” refer to one or to more than one (i.e. to at least one) of the grammatical object of the article.
  • “an element” means one element or more than one element.
  • use of the term“including” as well as other forms, such as “include”,“includes,” and“included,” is not limiting.
  • the term“about” will be understood by persons of ordinary skill in the art and will vary to some extent on the context in which it is used. As used herein when referring to a measurable value such as an amount, a temporal duration, and the like, the term“about” is meant to encompass variations of ⁇ 20% or ⁇ 10%, including ⁇ 5%, ⁇ 1%, and ⁇ 0.1% from the specified value, as such variations are appropriate to perform the disclosed methods.
  • capsid assembly modulator refers to a compound that disrupts or accelerates or inhibits or hinders or delays or reduces or modifies normal capsid assembly (e.g., during maturation) or normal capsid disassembly (e.g., during infectivity) or perturbs capsid stability, thereby inducing aberrant capsid morphology and function.
  • a capsid assembly modulator accelerates capsid assembly or disassembly, thereby inducing aberrant capsid morphology.
  • a capsid assembly modulator interacts (e.g.
  • a capsid assembly modulator causes a perturbation in structure or function of CA (e.g., ability of CA to assemble, disassemble, bind to a substrate, fold into a suitable conformation, or the like), which attenuates viral infectivity or is lethal to the virus.
  • treatment is defined as the application or administration of a therapeutic agent, i.e., a disclosed compound (alone or in combination with another pharmaceutical agent), to a patient, or application or administration of a therapeutic agent to an isolated tissue or cell line from a patient (e.g., for diagnosis or ex vivo applications), who has an HB V infection, a symptom of HBV infection or the potential to develop an HB V infection, with the purpose to cure, heal, alleviate, relieve, alter, remedy, ameliorate, improve or affect the HBV infection, the symptoms of HBV infection, or the potential to develop an HBV infection.
  • a therapeutic agent i.e., a disclosed compound (alone or in combination with another pharmaceutical agent
  • an isolated tissue or cell line from a patient (e.g., for diagnosis or ex vivo applications)
  • Such treatments may be specifically tailored or modified, based on knowledge obtained from the field of pharmacogenomics.
  • the term“prevent” or“prevention” means no disorder or disease development if none had occurred, or no further disorder or disease development if there had already been development of the disorder or disease. Also considered is the ability of one to prevent some or all of the symptoms associated with the disorder or disease.
  • the term“patient,”“individual” or“subject” refers to a human or a non-human mammal.
  • Non-human mammals include, for example, livestock and pets, such as ovine, bovine, porcine, canine, feline and murine mammals.
  • the patient, subject, or individual is human.
  • the terms “effective amount,” “pharmaceutically effective amount,” and “therapeutically effective amount” refer to a nontoxic but sufficient amount of an agent to provide the desired biological result. That result may be reduction or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. An appropriate therapeutic amount in any individual case may be determined by one of ordinary skill in the art using routine experimentation.
  • the term“pharmaceutically acceptable” refers to a material, such as a carrier or diluent, which does not abrogate the biological activity or properties of the compound, and is relatively non-toxic, i.e., the material may be administered to an individual without causing undesirable biological effects or interacting in a deleterious manner with any of the components of the composition in which it is contained.
  • the term“pharmaceutically acceptable salt” refers to derivatives of the disclosed compounds wherein the parent compound is modified by converting an existing acid or base moiety to its salt form.
  • pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like.
  • the pharmaceutically acceptable salts of the application include the conventional non-toxic salts of the parent compound formed, for example, from non-toxic inorganic or organic acids.
  • the pharmaceutically acceptable salts of the application can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods.
  • such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, non-aqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418 and Journal of Pharmaceutical Science, 66, 2 (1977), each of which is incorporated herein by reference in its entirety.
  • composition or“pharmaceutical composition” refers to a mixture of at least one compound of the application with a pharmaceutically acceptable carrier.
  • the pharmaceutical composition facilitates administration of the compound to a patient or subject. Multiple techniques of administering a compound exist in the art including, but not limited to, intravenous, oral, aerosol, parenteral, ophthalmic, pulmonary, and topical administration.
  • the term “pharmaceutically acceptable carrier” means a pharmaceutically acceptable material, composition or carrier, such as a liquid or solid filler, stabilizer, dispersing agent, suspending agent, diluent, excipient, thickening agent, solvent or encapsulating material, involved in carrying or transporting a compound of the application within or to the patient such that it may perform its intended function.
  • a pharmaceutically acceptable material, composition or carrier such as a liquid or solid filler, stabilizer, dispersing agent, suspending agent, diluent, excipient, thickening agent, solvent or encapsulating material, involved in carrying or transporting a compound of the application within or to the patient such that it may perform its intended function.
  • Such constructs are carried or transported from one organ, or portion of the body, to another organ, or portion of the body.
  • Each carrier must be“acceptable” in the sense of being compatible with the other ingredients of the formulation, including the compound of the application, and not injurious to the patient.
  • materials that may serve as pharmaceutically acceptable carriers include: sugars, such as lactose, glucose and sucrose; starches, such as corn starch and potato starch; cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients, such as cocoa butter and suppository waxes; oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols, such as propylene glycol; polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; esters, such as ethyl oleate and ethyl laurate; agar; buffering agents, such as magnesium hydroxide and aluminum hydroxide; surface active agents; alginic acid; pyrogen-free water; isotonic saline
  • “pharmaceutically acceptable carrier” also includes any and all coatings, antibacterial and antifungal agents, and absorption delaying agents, and the like that are compatible with the activity of the compound of the application and are physiologically acceptable to the patient. Supplementary active compounds may also be incorporated into the compositions.
  • the “pharmaceutically acceptable carrier” may further include a pharmaceutically acceptable salt of the compound of the application.
  • Other additional ingredients that may be included in the pharmaceutical compositions of the application are known in the art and described, for example in Remington's Pharmaceutical Sciences (Genaro, Ed., Mack Publishing Co., 1985, Easton, PA), which is incorporated herein by reference.
  • alkyl by itself or as part of another substituent means, unless otherwise stated, a straight or branched chain hydrocarbon having the number of carbon atoms designated (i.e., Ci-C 3 alkyl or C 1-3 alkyl means an alkyl having one to three carbon atoms, C 1 -C 4 alkyl or Ci- 4 alkyl means an alkyl having one to four carbon) and includes straight and branched chains. Examples include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl.
  • Embodiments of alkyl generally include, but are not limited to, C 1 -C 10 alkyl, such as C 1 -C 6 alkyl, such as C 1 -C 4 alkyl.
  • alkenyl by itself or as part of another substituent means, unless otherwise stated, a linear or branched chain of hydrocarbons comprising at least one carbon to carbon double bond, having the number of carbon atoms designated (i.e., C 2 -C 4 alkenyl or C 2 - 4 alkenyl means an alkenyl having two to four carbon atoms.
  • C 4 -C 8 alkenyl or Cri-xalkenyl means an alkenyl having four to eight carbon atoms.
  • halo or“halogen” alone or as part of another substituent means, unless otherwise stated, a fluorine (F), chlorine (Cl), bromine (Br), or iodine (I) atom, preferably, fluorine, chlorine, or bromine, more preferably, fluorine or chlorine.
  • saturated ring refers to saturated rings optionally contain one or more heteroatoms, the heteroatoms being independently selected from N, O and S.
  • the saturated ring is a cycloalkyl.
  • cycloalkyl refers to a mono cyclic non-aromatic saturated radical, wherein each of the atoms forming the ring (i.e., skeletal atoms) is a carbon atom.
  • C 3-6 cycloalkyl include groups having 3 to 6 ring atoms.
  • Such 3- to 6-membered saturated rings include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
  • the saturated ring contains one or more heteroatoms
  • these are independently selected from N, O and S.
  • the one or more heteroatoms independently selected from N, O and S will not be selected such as to provide a chemically non-existent structure.
  • this refers to chemistry that would not be considered aberrant by the skilled person.
  • the skilled person will be aware that, generally, in a single, 6-membered saturated ring, up to three nitrogen, oxygen, or sulfur atoms can be present.
  • saturated ring In a single, five- or six- membered saturated ring, several combinations of two heteroatoms can be present, such as nitrogen/nitrogen, nitrogen/oxygen, sulfur/nitrogen, oxygen/oxygen, and sulfur/sulfur. Generally, no adjacent bonds are present selected from the group consisting of O-O, S-N, S-S, and O-S.
  • saturated rings include, but are not limited to heterocyclyl groups comprising one, two or three heteroatoms, even more in particular, one or two, and most particular, one heteroatom. Said ring heteroatoms are each selected from O, S, and N.
  • each heterocyclyl group has from 3 to 6 atoms in its ring system, with the proviso that the ring of said group does not contain two adjacent O or S atoms.
  • the heterocyclyl group can be attached to the remainder of the molecule, unless otherwise stated, at any heteroatom or carbon atom that affords a stable structure.
  • An example of a 3-membered heterocyclyl group includes, and is not limited to, aziridine.
  • Examples of 4-membered heterocyclyl groups include, and are not limited to, azetidine and a beta lactam.
  • Examples of 5-membered heterocyclyl groups include, and are not limited to, pyrrolidine, oxazolidine and thiazolidinedione.
  • Examples of 6-membered heterocycloalkyl groups include, and are not limited to, piperidine, morpholine, and piperazine.
  • heterocyclyl groups include monocyclic groups such as aziridine, oxirane, thiirane, azetidine, oxetane, thietane, pyrrolidine, pyrroline, pyrazolidine, imidazoline, dioxolane, sulfolane, tetrahydrofuran, thiophane, piperidine, piperazine, morpholine, thiomorpholine.
  • aromatic refers to a carbocycle or heterocycle with one or more polyunsaturated rings and having aromatic character, i.e., having (4n + 2) delocalized p (pi) electrons, where n is an integer.
  • aryl means, unless otherwise stated, a carbocyclic aromatic system containing one or more rings (typically one, two, or three rings), wherein such rings may be attached together in a pendent manner, such as a biphenyl, or may be fused, such as naphthalene.
  • aryl groups include phenyl, anthracyl, and naphthyl. Preferred examples are phenyl (e.g., C 6 -aryl) and biphenyl (e.g., Ci2-aryl).
  • aryl groups have from six to sixteen carbon atoms.
  • aryl groups have from six to twelve carbon atoms (e.g., C6-Ci2-aryl).
  • aryl groups have six carbon atoms (e.g., C 6 -aryl).
  • heteroaryl or“heteroaromatic” refers to a heterocycle having aromatic character.
  • aromatic character the skilled person is aware of the customary limitations to the number of ring atoms.
  • heteroaryl substituents may be defined by the number of carbon atoms, e.g., Ci-i2heteroaryl, such as C3-9 indicates the number of carbon atoms contained in the heteroaryl group without including the number of heteroatoms.
  • a Ci-C9-heteroaryl will include an additional one to four heteroatoms.
  • heteroaryl substituents may be defined by the total number of atoms (carbon(s) and heteroatom(s)) in the ring, e.g. 5-membered, 6-membered.
  • a polycyclic heteroaryl may include one or more rings that are partially saturated.
  • heteroaryls include pyridyl, pyrazinyl, pyrimidinyl (including, e.g., 2- and 4-pyrimidinyl), pyridazinyl, thienyl, furyl, pyrrolyl (including, e.g., 2-pyrrolyl), imidazolyl, thiazolyl, oxazolyl, pyrazolyl (including, e.g., 3- and 5-pyrazolyl), isothiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,3,4-triazolyl, tetrazolyl, 1,2,3-thiadiazolyl, 1,2,3-oxadiazolyl, 1,3,4-thiadiazolyl and 1,3,4-oxadiazolyl.
  • Non-limiting examples of polycyclic, such as bicyclic, heterocycles and heteroaryls include indolyl (including, e.g., 3-, 4-, 5-, 6- and 7-indolyl), indolinyl, quinolyl, tetrahydroquinolyl, isoquinolyl (including, e.g., 1- and 5-isoquinolyl), 1,2,3,4-tetrahydroisoquinolyl, cinnolinyl, quinoxalinyl (including, e.g., 2- and 5-quinoxalinyl), quinazolinyl, phthalazinyl,
  • 1,2-benzisoxazolyl benzothienyl (including, e.g., 3-, 4-, 5-, 6-, and 7-benzothienyl), benzoxazolyl, benzothiazolyl (including, e.g., 2-benzothiazolyl and 5-benzothiazolyl), purinyl, benzimidazolyl (including, e.g., 2-benzimidazolyl), benzotriazolyl, thioxanthinyl, carbazolyl, carbolinyl, acridinyl, pyrrolizidinyl, and quinolizidinyl.
  • substituted means that an atom or group of atoms has replaced hydrogen as the substituent attached to another group.
  • the application provides a compound of formula (I): including the stereoisomers or tautomeric forms thereof, or a pharmaceutically acceptable salt thereof, wherein: represents a 6-membered aryl ring optionally containing one or more heteroatom(s), wherein the heteroatom or each of the heteroatoms is or are more particularly nitrogen (i.e., wherein represents a 6-membered aryl ring optionally containing one or more nitrogen atom(s));
  • R 1 , R 2 and R 3 are each independently selected from the group consisting of H, F, Cl, Br, CHF 2 , CH 2 F, CF 3 , CN, Ci- 4 alkyl and C 3-6 cycloalkyl;
  • R 4 is selected from the group consisting of H and F;
  • R 5a and R 5b are selected from the group consisting of H, Ci- 4 alkyl optionally substituted with one or more F, and C 3-6 cycloalkyl optionally substituted with one or more F;
  • R 6a and R 6b are selected from the group consisting of H, Ci- 4 alkyl optionally substituted with one or more F, and C 3-6 cycloalkyl optionally substituted with one or more F;
  • R 7a and R 7b are selected from the group consisting of H, Ci- 4 alkyl optionally substituted with one or more F, and C 3-6 cycloalkyl optionally substituted with one or more F;
  • Q is selected from the group consisting of
  • Ci-salkyl optionally substituted with one or more substituents selected from the group consisting of halogens;
  • heteroatoms optionally (and independently) contain one or more heteroatoms, the heteroatoms being independently selected from N, O and S, and/or
  • R 8 is H
  • R 9 is selected from the group consisting of phenyl
  • phenyl substituted with one or more substituents selected from the group consisting of halogens, CN, CF 3 , CF 2 H, CFFF, Ci- 4 alkyl, C 3-6 cycloalkyl, OH and OCi- 4 alkyl,
  • pyrimidyl substituted with one or more substituents selected from the group consisting of halogens, CN, CF 3 , CF 2 H, CH 2 F, Ci- 4 alkyl, C 3-6 cycloalkyl, OH and OCi- 4 alkyl,
  • pyrazinyl substituted with one or more substituents selected from the group consisting of halogens, CN, CF 3 , CF 2 H, CH 2 F, Ci- 4 alkyl, C 3-6 cycloalkyl, OH and OCi- 4 alkyl,
  • pyridazinyl substituted with one or more substituents selected from the group consisting of halogens, CN, CF 3 , CF 2 H, CH 2 F, Ci- 4 alkyl, C 3-6 cycloalkyl, OH and OCi- 4 alkyl,
  • heteroatoms 5-membered unsaturated heterocycles containing one to 4 heteroatoms, the heteroatoms being independently selected from N, O and S, and
  • 5-membered unsaturated heterocycles containing one to 4 heteroatoms the heteroatoms being independently selected from N, O and S, substituted with one or more substituents selected from the group consisting of halogens, CN, CF 3 , CF 2 H, C3 ⁇ 4F, Ci- 4 alkyl, C 3-6 cycloalkyl, OH and OCi- 4 alkyl.
  • Q is a Ci-4alkyl substituted with one or more halogens, in particular fluoro; or is a 3- to 6-membered monocyclic saturated ring containing one substituted with one or more substituents selected from the group consisting of F and Ci-4alkyl substituted with one or more F.
  • Q is a 3- to 6-membered monocyclic saturated ring containing one substituted with one or more substituents selected from the group consisting of F and Ci-4alkyl substituted with one or more F.
  • R 9 is a 5-membered unsaturated heterocycle containing one to 4 heteroatoms, the heteroatoms being selected from N, O and S, and optionally substituted with one or more substituents selected from the group consisting of halogens, CN, CF3, CF2H, CHF2, Ci-4alkyl, C3-6cycloalkyl, OH and OCi-4alkyl.
  • substituents selected from the group consisting of halogens, CN, CF3, CF2H, CHF2, Ci-4alkyl, C3-6cycloalkyl, OH and OCi-4alkyl.
  • R 9 is a triazolyl and optionally substituted with one or more substituents selected from the group consisting of halogens and Ci-4alkyl; more in particular, R 9 is a lH-l,2,3-triazolyl-4-yl or 4-methyl-l,2,3-triazol-4-yl.
  • R 1 , R 2 and R 3 are each independently selected from the group consisting of H, F, Cl, Br, CHF 2 , CF 3 , CN, and Ci-4alkyl; and R 4 is H or F.
  • R 1 is H
  • R 2 is H or F
  • R 3 is Cl
  • CN or F is F
  • each of R 1 and R 2 is H, R 3 is Cl or CN, and R 4 is F.
  • R 1 is H
  • each of R 2 , R 3 and R 4 is F.
  • ' ⁇ ' represents phenyl or pyridyl.
  • ' ⁇ ' represents phenyl
  • ' ⁇ ' is selected from the group consisting of:
  • Q may more particularly be CH 2 CF 3 or cyclobutyl substituted with one or more fluorine, more particularly difluorocyclobutyl, more particularly 3,3- difluorocyclobutyl .
  • Q may more particularly be cyclobutyl substituted with one or more fluorine, more particularly difluorocyclobutyl, more particularly 3,3- difluorocyclobutyl .
  • Q is CH 2 CF 3 or 3, 3 -difluorocyclobutyl.
  • Q may more particularly be cyclobutyl substituted with one or more fluorine, more particularly difluorocyclobutyl, more parti cul arly 3 , 3 -difluorocy cl obuty 1.
  • Q is 3- to 6-membered monocyclic saturated rings, wherein the (3- to 6-membered monocyclic) saturated rings:
  • heteroatoms optionally (and independently) contain one or more heteroatoms, the heteroatoms being independently selected from N, O and S, and/or
  • R 5a and R 5b are each independently selected from the group consisting of H and methyl;
  • R 6a and R 6b are each independently selected from the group consisting of H and methyl;
  • R 7a and R 7b are each independently selected from the group consisting of H and methyl.
  • R 5a is methyl and R 5b is H;
  • R 6a and R 6b are H;
  • R 7a and R 7b are each independently selected from the group consisting of H and methyl.
  • R 5a and R 5b are H;
  • R 6a and R 6b are H;
  • R 7a is methyl and R 7b is H.
  • compounds in accordance with the application include, but are not limited to compounds having the formula Cl, C1*HC1, C2, C3, C4, C5 or C6 (cf. Table 1 above).
  • compounds in accordance with the application include, but are not limited to compounds having the formula chosen from among formulas Cl, C1*HC1, C2, C4 and C5 (cf. Table 1 above).
  • compounds in accordance with the application include, but are not limited to compounds having the formula chosen from among formulas C3 and C6 (cf. Table 1 above). More particularly, compounds in accordance with the application include, but are not limited to compounds having the formula chosen from among formulas C3 and C4 (cf. Table 1 above).
  • compounds in accordance with the application include, but are not limited to compounds having the formula chosen from among formulas Cl, C1*HC1, C2, C5 and C6 (cf. Table 1 above).
  • the disclosed compounds may possess one or more stereocenters, and each stereocenter may exist independently in either R or S configuration.
  • the stereochemical configuration may be assigned at indicated centers as (*R), (*S), (R*) or (S*) when the absolute stereochemistry is undetermined although the compound itself has been isolated as a single stereoisomer and is enantiomerically/diastereomerically pure.
  • the compounds described herein encompass racemic, optically-active, regioisomeric and stereoisomeric forms, or combinations thereof that possess the therapeutically useful properties described herein.
  • the absolute configuration is specified according to the Cahn- Ingold-Prelog system. When the absolute R or S stereochemistry of a compound cannot be determined, it can be identified by the retention time after chromatography under particular chromatographic conditions as determined by chromatographic column, eluent etc.
  • a stereoisomeric form of a compound refers to all possible compounds made up of the same atoms bonded by the same sequence of bonds but having different three-dimensional structures which are not interchangeable.
  • Preparation of optically active forms is achieved in any suitable manner, including by way of non limiting example, by resolution of the racemic form with recrystallization techniques, synthesis from optically-active starting materials, chiral synthesis, or chromatographic separation using a chiral stationary phase.
  • a mixture of one or more isomers can be utilized as the disclosed compound described herein.
  • Compounds described herein may contain one or more chiral centers. These compounds can be prepared by any means, including stereoselective synthesis, enantioselective synthesis or separation of a mixture of enantiomers or diastereomers. Resolution of compounds and isomers thereof can be achieved by any means including, by way of non limiting example, chemical processes, enzymatic processes, fractional crystallization, distillation, and chromatography.
  • the disclosed compounds may exist as tautomers.
  • A“tautomer” refers to a proton-shift from one atom of the molecule to another atom of the same molecule. All tautomers are included within the scope of the compounds presented herein.
  • Compounds described herein also include isotopically-labeled compounds wherein one or more atoms are replaced by an atom having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
  • isotopes suitable for inclusion in the compounds described herein include and are not limited to 3 ⁇ 4, 3 ⁇ 4, U C, 13 C, 14 C, 36 C1, 18 F, 123 I, 125 I, 13 N, 15 N, 15 0, 17 0, 18 0, 32 P, and 35 S.
  • Isotopically-labeled compounds can be useful in drug or substrate tissue distribution studies. Substitution with heavier isotopes such as deuterium may afford greater metabolic stability (which may lead to for example, increased in vivo half-life or reduced dosage requirements).
  • Isotopically- lab el ed compounds can be prepared by any suitable method or by processes using an appropriate isotopically-labeled reagent in place of the non-labeled reagent otherwise employed.
  • the compounds described herein may be labeled by other means, including, but not limited to, the use of chromophores or fluorescent moieties, bioluminescent labels, or chemiluminescent labels.
  • the compounds described herein, and other related compounds having different substituents can be synthesized using techniques and materials described herein and techniques known to the person of average skill in the art. General methods for the preparation of compound as described herein can be modified by the use of appropriate reagents and conditions, for the introduction of the various moieties found in the formula as provided herein.
  • a compound of the application may be useful for reducing viral load associated with an HBV infection in an individual in need thereof, e.g., by administering to an individual in need thereof a therapeutically effective amount of a disclosed compound.
  • a compound of the application may be useful for reducing reoccurrence of an HBV infection in an individual in need thereof, e.g., by administering to an individual in need thereof a therapeutically effective amount of a disclosed compound.
  • a compound of the application may be useful for inhibiting or reducing the formation or presence of HBV DNA-containing particles or HBV RNA-containing particles in an individual in need thereof, e.g., by administering to the individual a therapeutically effective amount of a disclosed compound.
  • a compound of the application can be useful for reducing an adverse physiological impact of an HBV infection in an individual in need thereof, e.g., by administering to the individual a therapeutically effective amount of a disclosed compound.
  • a compound of the application may be useful for reducing, slowing, or inhibiting an HBV infection in an individual in need thereof, e.g., by administering to the individual a therapeutically effective amount of a disclosed compound.
  • a compound of the application may be useful for inducing reversal of hepatic injury from an HBV infection in an individual in need thereof, e.g., by administering to the individual a therapeutically effective amount of a disclosed compound.
  • a compound of the application may be useful for reducing the physiological impact of long-term antiviral therapy for HBV infection in an individual in need thereof, e.g., by administering to the individual a therapeutically effective amount of a disclosed compound.
  • a compound of the application may be useful for prophylactically treating an HBV infection in an individual in need thereof, wherein the individual is afflicted with a latent HBV infection, e.g., by administering to the individual a therapeutically effective amount of a disclosed compound.
  • a compound of the application may be useful for increasing or normalizing or restoring normal health, or eliciting full recovery of normal health, or restoring life expectancy, or resolving the viral infection in the individual in need thereof.
  • the application relates to a pharmaceutical composition, which comprises at least one compound or pharmaceutically acceptable salt as herein described, and which further comprises at least one pharmaceutically acceptable carrier.
  • the application relates to such a compound or pharmaceutically acceptable salt, or to such a pharmaceutical composition, for use as a medicament.
  • the application relates to such a compound or pharmaceutically acceptable salt, or to such a pharmaceutical composition, for use in the prevention or treatment of an HBV infection or of an HBV-induced disease in mammal in need thereof.
  • the application relates to such a compound or pharmaceutically acceptable salt, or to such a pharmaceutical composition, for use in the prevention, the prevention of aggravation, the amelioration or the treatment of chronic Hepatitis B.
  • the application relates to such a compound or pharmaceutically acceptable salt, or to such a pharmaceutical composition, for use in the prevention, the prevention of aggravation, the amelioration or the treatment of a HBV-induced disease or condition.
  • HBV-induced disease or condition includes progressive liver fibrosis, inflammation and necrosis leading to cirrhosis, end-stage liver disease, and hepatocellular carcinoma. Additionally, HBV acts as a helper virus to hepatitis delta virus (HDV), and it is estimated that more than 15 million people may be HBV/HDV co-infected worldwide, with an increased risk of rapid progression to cirrhosis and increased hepatic decompensation, than patients suffering from HBV alone (Hughes, S.A. et al. Lancet 2011, 378, 73-85). HDV, infects therefore subjects suffering from HBV infection.
  • HDV hepatitis delta virus
  • the compounds of the invention may be used in the treatment and/or prophylaxis of HBV/HDV co-infection, or diseases associated with HBV/HDV co infection. Therefore, in a particular embodiment, the HBV infection is in particular HBV/HDV co-infection, and the mammal, in particular the human, may be HBV/HDV co-infected, or be at risk of HBV/HDV co infection.
  • the application relates to such a compound or pharmaceutically acceptable salt, or to such a pharmaceutical composition, for any of the above-mentioned uses, more particularly for use in the prevention, the prevention of aggravation, the amelioration, or the treatment of one or more of the following items:
  • chronic hepatis infection more particularly chronic hepatis B infection (ie, preventing that the hepatitis (B) infection becomes chronic);
  • a hepatitis-associated or hepatitis-induced (chronic) disease or condition more particularly of a hepatitis B-associated or hepatitis B-induced (chronic) disease or condition;
  • the amelioration (reduction) of the fibrosis progression rate of a (chronic) hepatitis infection more particularly the prevention of cirrhosis in a subject having a (chronic) hepatitis infection, more particularly by a (chronic) hepatitis B infection (e.g., preventing that the subject reaches the cirrhotic stage of fibrosis).
  • the compounds of the application may exist in unsolvated and solvated forms.
  • solvate is used herein to describe a molecular complex comprising the compound of the application and one or more pharmaceutically acceptable solvent molecules, for example, ethanol.
  • polymorph refers to the ability of the compound of the application to exist in more than one form or crystal structure.
  • the compounds of the application may be administered as crystalline or amorphous products. They may be obtained for example as solid plugs, powders, or films by methods such as precipitation, crystallization, freeze drying, spray drying, or evaporative drying. They may be administered alone or in combination with one or more other compounds of the application or in combination with one or more other drugs. Generally, they will be administered as a formulation in association with one or more pharmaceutically acceptable excipients.
  • excipient is used herein to describe any ingredient other than the compound(s) of the application. The choice of excipient depends largely on factors such as the particular mode of administration, the effect of the excipient on solubility and stability, and the nature of the dosage form.
  • the application also relates to a product comprising a first compound and a second compound as a combined preparation for simultaneous, separate or sequential use in the prevention or treatment of an HBV infection or of an HBV-induced disease in mammal in need thereof, wherein said first compound is different from said second compound, wherein said first compound is the compound or pharmaceutically acceptable salt as herein described, or the pharmaceutical composition of the application, and wherein said second compound is another HBV inhibitor.
  • a second compound is another HBV inhibitor which is selected from the group consisting HBV combination drugs, HBV DNA polymerase inhibitors, immunomodulators, toll like (TLR) receptor modulators, interferon alpha receptor ligands, hyaluronidase inhibitors, hepatitis b surface antigen (HbsAg) inhibitors, cytotoxic T-lymphocyte-associated protein 4 (ipi4) inhibitors, cyclohilin inhibitors, HBV viral entry inhibitors, antisense oligonucleotide targeting viral mRNA, short interfering RNAs (siRNA) and ddRNAi endonuclease modulators, ribonucleotide reductase inhibitors, HBV E antigen inhibitors, covalently closed circular DNA (cccDNA) inhibitors, farnsoid X receptor agonists, HBV antibodies, CCR2 chemokine antagonists, thymosin agonists, cytokines, nucleo
  • compositions of the application may be formulated into various pharmaceutical forms for administration purposes.
  • compositions there may be cited all compositions usually employed for systemically administering drugs.
  • an effective amount of the particular compound, optionally in addition salt form, as the active ingredient is combined in intimate admixture with a pharmaceutically acceptable carrier, which carrier may take a wide variety of forms depending on the form of preparation desired for administration.
  • a pharmaceutically acceptable carrier which carrier may take a wide variety of forms depending on the form of preparation desired for administration.
  • These pharmaceutical compositions are desirably in unitary dosage form suitable, for example, for oral, rectal, or percutaneous administration.
  • any of the usual pharmaceutical media may be employed such as, for example, water, glycols, oils, alcohols and the like in the case of oral liquid preparations such as suspensions, syrups, elixirs, emulsions, and solutions; or solid carriers such as starches, sugars, kaolin, diluents, lubricants, binders, disintegrating agents and the like in the case of powders, pills, capsules, and tablets. Because of their ease in administration, tablets and capsules represent the most advantageous oral dosage unit forms, in which case solid pharmaceutical carriers are obviously employed. Also included are solid form preparations that can be converted, shortly before use, to liquid forms.
  • the carrier optionally comprises a penetration enhancing agent and/or a suitable wetting agent, optionally combined with suitable additives of any nature in minor proportions, which additives do not introduce a significant deleterious effect on the skin. Said additives may facilitate the administration to the skin and/or may be helpful for preparing the desired compositions.
  • These compositions may be administered in various ways, e.g., as a transdermal patch, as a spot-on, as an ointment.
  • the compounds of the application may also be administered via inhalation or insufflation by means of methods and formulations employed in the art for administration via this way.
  • the compounds of the application may be administered to the lungs in the form of a solution, a suspension or a dry powder.
  • Unit dosage form refers to physically discrete units suitable as unitary dosages, each unit containing a predetermined quantity of active ingredient calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier.
  • unit dosage forms are tablets (including scored or coated tablets), capsules, pills, powder packets, wafers, suppositories, injectable solutions or suspensions and the like, and segregated multiples thereof.
  • an effective daily amount would be from 0.01 mg/kg to 50 mg/kg body weight, more preferably from 0.1 mg/kg to 10 mg/kg body weight. It may be appropriate to administer the required dose as two, three, four or more sub-doses at appropriate intervals throughout the day. Said sub-doses may be formulated as unit dosage forms, for example, containing 1 to 1000 mg, and in particular 5 to 200 mg of active ingredient per unit dosage form.
  • the exact dosage and frequency of administration depends on the particular compound of formula (I) used, the particular condition being treated, the severity of the condition being treated, the age, weight and general physical condition of the particular patient as well as other medication the individual may be taking, as is well known to those skilled in the art. Furthermore, it is evident that the effective amount may be lowered or increased depending on the response of the treated subject and/or depending on the evaluation of the physician prescribing the compounds of the application. The effective amount ranges mentioned above are therefore only guidelines and are not intended to limit the scope or use of the application to any extent.
  • R 8 , R 9 and Q have the abovementioned meaning.
  • the term“comprising” hence includes the term“consisting of’ (“consist(s) of’), as well as the term“essentially consisting of’ (“essentially consist(s) of’). Accordingly, the term“comprising” (or“comprise(s)”) is, in the present application, meant as more particularly encompassing the term“consisting of’ (“consist(s) of’), and the term“essentially consisting of’ (“essentially consist(s) of’).
  • the description has been separated in various paragraphs or sections. These separations should not be considered as disconnecting the substance of a paragraph or section from the substance of another paragraph or section. To the contrary, the present description encompasses all the combinations of the various sections, paragraphs and sentences that can be contemplated.
  • HPLC High Performance Liquid Chromatography
  • MS Mass Spectrometer
  • tune parameters e.g. scanning range, dwell time
  • ions allowing the identification of the compound’s nominal monoisotopic molecular weight (MW).
  • Data acquisition was performed with appropriate software.
  • Compounds are described by their experimental retention times (Rt) and ions. If not specified differently in the table of data, the reported molecular ion corresponds to the [M+H] + (protonated molecule) and/or [M-H] (deprotonated molecule). In case the compound was not directly ionizable the type of adduct is specified (i.e. [M+NH 4 ] + , [M+HCOO] , etc). All results were obtained with experimental uncertainties that are commonly associated with the method used.
  • “SQD” means Single Quadrupole Detector,“MSD” Mass Selective Detector,“RT” room temperature,“BEH” bridged ethylsiloxane/silica hybrid,“DAD” Diode Array Detector, “HSS” High Strength silica.,“Q-Tof” Quadrupole Time-of-flight mass spectrometers,“CLND”, ChemiLuminescent Nitrogen Detector,“ELSD” Evaporative Light Scanning Detector,
  • the SFC measurement was performed using an Analytical Supercritical fluid chromatography (SFC) system composed by a binary pump for delivering carbon dioxide (C02) and modifier, an autosampler, a column oven, a diode array detector equipped with a high-pressure flow cell standing up to 400 bars. If configured with a Mass Spectrometer (MS) the flow from the column was brought to the (MS). It is within the knowledge of the skilled person to set the tune parameters (e.g. scanning range, dwell time%) in order to obtain ions allowing the identification of the compound’ s nominal monoisotopic molecular weight (MW). Data acquisition was performed with appropriate software.
  • SFC Analytical Supercritical fluid chromatography
  • the reaction was performed under anhydrous conditions and under Ar atmosphere.
  • the reaction was performed under anhydrous conditions and under Ar atmosphere.
  • Step 2 The reaction was performed in anhydrous conditions under Ar atmosphere.
  • the reaction was performed in anhydrous conditions under Argon atmosphere.
  • the reaction was performed under Argon atmosphere.
  • the reaction was performed in anhydrous conditions under Ar atmosphere.
  • the reaction was performed in anhydrous conditions under Ar atmosphere.
  • Step 2 The reaction was performed in anhydrous conditions under Ar atmosphere
  • Step 4 The reaction was performed under hydrogen atmosphere
  • the reaction mixture was purged and backfilled with argon twice then purged and backfilled with hydrogen and stirred at rt for 6h.
  • the catalyst was filtered through a pad of Celite® and rinsed with MeOH (50 mL) and the filtrate was concentrated in vacuo.
  • the residue was suspended in EtOAc (200 mL) and the resulting solid (Et3N.HCl) was removed by filtration.
  • the filtrate was concentrated in vacuo.
  • the crude mixture was purified by chromatography (silica, dry load, mobile phase: cyclohexane/EtOAc, gradient from 100/0 to 85/15).
  • reaction mixture was diluted with water (30 mL), acidified with HC1 (3N, aq.,) until pH ⁇ 1 and extracted with EtOAc (3 x 100 mL). Combined organic layers were washed with brine, dried (Na 2 S0 4 ), filtered and concentrated to afford 2-oxo-2-((3,3,3-trifluoro-l-(lH-l,2,3-triazol-4-yl)propyl)amino)acetic acid 169 (511 mg, 95%, 87% purity) as a white solid which was used as such in the next step.
  • the reaction was performed in anhydrous conditions, under Argon atmosphere
  • the reaction was performed in anhydrous conditions under Argon atmosphere.
  • tert-butyl (5,5-difluoro-3-methylpent-l- yn-3-yl)carbamate 181 (1.02 g, 92%) as a white powder which was used in next step without further purification.
  • tert-butyl (5,5-difluoro-3-methylpent-l-yn-3-yl)carbamate 181 (1.02 g, 4.37 mmol) in a mixture of DMF (8 mL) and MeOH (0.8 mL) at room temperature were added azidotrimethylsilane (1.61 mL, 12.24 mmol) and copper iodide (42 mg, 0.22 mmol).
  • the reaction mixture was stirred at 100°C for 7 h.
  • the reaction mixture was diluted with EtOAc (100 mL) and the organic layer was washed with brine (2x100 mL), dried (Na 2 S0 4 ), filtered and concentrated to dryness.
  • the reaction was performed in anhydrous conditions under argon.
  • reaction mixture was concentrated to dryness and co-evaporated with DCM (2x20mL) to afford 4,4-difluoro-2-(lH- l,2,3-triazol-4-yl)butan-2-amine hydrochloride 183 (540 mg, quant.) as a white powder which was used in next step without further purification.
  • the reaction was performed in anhydrous conditions under argon atmosphere.
  • the reaction was stirred at rt for 4 h.
  • the reaction mixture was diluted with water (100 mL) and extracted with EtOAc (3 x 100 mL). Combined organic layers were washed with brine, dried over (NaiSCL), filtered and concentrated.
  • the crude was purified by flash chromatography (silica, mobile phase: cyclohexane/EtOAc, gradient from 100/0 to 5/5) to afford tert-butyl (3-(difluoromethyl)-l-(hydroxymethyl)cyclobutyl)carbamate 184 (804 mg, 70%, 83 % purity) as a white solid.
  • the reaction was performed under anhydrous conditions and under Ar atmosphere.
  • the reaction was performed under anhydrous conditions and under Ar atmosphere.
  • intermediate 115 (0.23 g, 0.73 mmol) in DMF (2.5 mL) were added intermediate 124 (146 g, 0.87 mmol), PPACA (0.38 mL, 2.18 mmol, 50% purity) and DIPEA (0.65 mL, 1.09 mmol).
  • the reaction mixture was stirred at room temperature for 75 h and diluted with EtOAc (80 mL).
  • the organic layer was successively washed with NaHCCb (sat., aq., 2 x 80 mL), HC1 (IN, aq., 2 x 80 mL) and brine (2 x 80 mL), dried (NaiSCL), filtered and concentrated to dryness.
  • the crude mixture was purified by flash column chromatography (silica, mobile phase: DCM/MeOH, gradient from 100:0 to 95:5) to afford intermediate 125 (200 mg, 59%, 92% purity).
  • the reaction was performed under anhydrous conditions and under Ar atmosphere.
  • intermediate 125 (0.20 g, 0.43 mmol, 92% purity) in a mixture of DMF (0.4 mL) and MeOH (0.045 mL) were added azidotrimethylsilane (85 pL, 0.64 mmol) and Cul (4.10 mg, 22 pmol).
  • the reaction mixture was stirred at 100 °C using a single mode microwave (Biotage Initiator EXP60 system) for 20 min, then 10 min and again 10 min.
  • the reaction mixture was filtered under PTFE filter.
  • the filtrate was diluted with EtOAc (100 mL) and the organic layer was washed with NELOH (aq., 2 x 100 mL) and brine (2 x 100 mL), dried (NaiSCL), filtered and concentrated to dryness.
  • the crude was purified by flash column chromatography (silica, mobile phase: DCM/MeOH, gradient from 100:0 to 95:5).
  • a second purification was performed by flash column chromatography (C18, mobile phase: CEbCN (0.05% ElCOOHyELO (0.1% HCOOH), gradient from 0: 100 to 40:60).
  • the reaction was performed under anhydrous conditions and under Ar atmosphere.
  • intermediate 17 hydrochloride 240 mg, 1.14 mmol
  • PPACA PPACA
  • DIPEA 497 pL, 2.85 mmol
  • the reaction mixture was stirred at room temperature for 18 h.
  • the reaction mixture was combined with another fraction (0.16 mmol) and diluted with water (30 mL).
  • the aqueous phase was extracted with EtOAc (3 x 40 mL).
  • the combined organic layers were washed with brine (2 x 40 mL), dried (Na 2 S0 4 ), filtered and concentrated under vacuum.
  • the anti HBV activity was measured using the HepG2.117 cell line, a stable, inducible HBV producing cell line, which replicates HBV in the absence of doxicycline (Tet-off system).
  • the HepG2 cell line is available from ATCC® under number HB-8065. Transfection of the HepG2 cell line can be as described in Sun and Nassal 2006 Journal of Hepatology 45 (2006) 636-645 Stable HepG2- and Huh7 -based human hepatoma cell lines for efficient regulated expression of infectious hepatitis B virus" .
  • HBV replication was induced, followed by a treatment with serially diluted compound in 96-well plates. After 3 days of treatment, the antiviral activity was determined by quantification of intracellular HBV DNA using real-time PCR and an HBV specific primer set and probe.
  • Cytotoxicity of the compounds was tested using HepG2 or HepG2.117 cells, incubated for 3 days in the presence of compounds. The viability of the cells was assessed using the Perkin Elmer ATPlite Luminescence Assay System.”
  • HepG2.117 cells were cultured in the presence of DMSO or test compound in absence of doxycycline.
  • Hepatitis B virus core protein (HBc) was immunolabeled with a primary anti-HBc antibody.
  • ALEXA 488-conjugated secondary antibody was used for fluorescent detection of the primary HBV Core signal.
  • CELLMASK Deep Red and HOECHST 33258 were used for the detection of cytoplasm and nucleus respectively, which allowed the segmentation of cellular compartments.
  • An image analysis software that allows to detect different morphological phenotypes was used to determine the level of HBV core in the cytoplasm or nucleus (high content imaging assay).

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EP20725652.0A 2019-05-06 2020-05-05 In der behandlung einer hbv-infektion oder von hbv-induzierten erkrankungen nützliche amidderivate Withdrawn EP3966205A1 (de)

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3843662A (en) 1971-12-09 1974-10-22 Pfizer 2-halo-5-(substituted piperidino sulfonyl)benzoic acids
AU1508183A (en) 1982-06-04 1983-12-08 Beecham Group Plc Benzamide and anilide derivatives of 8-azabicyclo-(3.2.1)- -octane
EP0135545A1 (de) 1983-02-19 1985-04-03 Beecham Group Plc Azabicycloalkyl-derivate von benzamid und anilid
JPS62142164A (ja) 1985-12-13 1987-06-25 Ishihara Sangyo Kaisha Ltd ４，５−ジクロロイミダゾ−ル系化合物及びそれらを含有する有害生物防除剤
IN164880B (de) 1986-01-30 1989-06-24 Ishihara Sangyo Kaisha
US5272167A (en) 1986-12-10 1993-12-21 Schering Corporation Pharmaceutically active compounds
CA1339133C (en) 1987-03-13 1997-07-29 Rikuo Nasu Imidazole compounds and biocidal composition comprising the same for controlling harmful organisms
US5571821A (en) 1993-05-20 1996-11-05 Texas Biotechnology Corporation Sulfonamides and derivatives thereof that modulate the activity of endothelin
GB8904174D0 (en) 1989-02-23 1989-04-05 British Bio Technology Compounds
US4962101A (en) 1989-08-21 1990-10-09 Merck & Co., Inc. 2-(Heterocyclylalkyl)phenyl carbapenem antibacterial agents
GB9023082D0 (en) 1990-10-24 1990-12-05 Schering Agrochemicals Ltd Fungicides
GB9109557D0 (en) 1991-05-02 1991-06-26 Wellcome Found Chemical compounds
US5308826A (en) 1993-04-22 1994-05-03 Zeneca Limited Herbicidal 4-substituted pyridyl-3-carbinols
GB9405347D0 (en) 1994-03-18 1994-05-04 Agrevo Uk Ltd Fungicides
US5795907A (en) 1994-05-27 1998-08-18 James Black Foundation Limited Gastin and CCK receptor ligands
WO1995032949A1 (en) 1994-05-27 1995-12-07 James Black Foundation Limited Gastrin and cck antagonists
US5763618A (en) 1995-05-12 1998-06-09 Konica Corporation Manufacturing method of sulfides
US5723411A (en) 1995-10-31 1998-03-03 E. I. Du Pont De Nemours And Company Herbicidal pyridazinones
DE19540995A1 (de) 1995-11-03 1997-05-07 Hoechst Ag Substituierte Sulfonimidamide, Verfahren zu ihrer Herstellung, ihre Verwendung als Medikament oder Diagnostikum sowie sie enthaltendes Medikament
GB9612884D0 (en) 1996-06-20 1996-08-21 Smithkline Beecham Plc Novel compounds
WO1997049695A1 (en) 1996-06-25 1997-12-31 Smithkline Beecham P.L.C. Sulfonamide derivatives as 5ht7 receptor antagonists
AU5127098A (en) 1996-11-29 1998-06-22 Smithkline Beecham Plc Use of a combination of penciclovir and alpha-interferon in the manufacture of a medicament for the treatment of hepatitis
US5939423A (en) 1997-04-16 1999-08-17 Sciclone Pharmaceuticals, Inc. Treatment of hepatitis B infection with thymosin alpha 1 and famciclovir
US5919970A (en) 1997-04-24 1999-07-06 Allergan Sales, Inc. Substituted diaryl or diheteroaryl methanes, ethers and amines having retinoid agonist, antagonist or inverse agonist type biological activity
US5994396A (en) 1997-08-18 1999-11-30 Centaur Pharmaceuticals, Inc. Furansulfonic acid derivatives and pharmaceutical compositions containing the same
AU759255B2 (en) 1998-01-29 2003-04-10 Amgen, Inc. PPAR-gamma modulators
BR9909666A (pt) 1998-03-26 2001-09-11 Japan Tobacco Inc Derivados de amida e antagonistas de nociceptina
US6251893B1 (en) 1998-06-15 2001-06-26 Nps Allelix Corp. Bicyclic piperidine and piperazine compounds having 5-HT6 receptor affinity
CZ300366B6 (cs) 1999-01-15 2009-05-06 Nycomed Gmbh Fenylfenanthridinová sloucenina, farmaceutický prostredek s jejím obsahem a její použití
KR20020015376A (ko) 1999-07-16 2002-02-27 로즈 암스트롱, 크리스틴 에이. 트러트웨인 Ｍｅｋ 억제제를 사용한 만성 통증의 치료 방법
JP2003506406A (ja) 1999-08-10 2003-02-18 ザ・チャンセラー・マスターズ・アンド・スカラーズ・オブ・ザ・ユニバーシティ・オブ・オックスフォード 長鎖ｎ−アルキル化合物およびそのオキサ誘導体
CA2385592C (en) 1999-09-17 2011-01-11 Bing-Yan Zhu Benzamides and related inhibitors of factor xa
PE20010628A1 (es) 1999-10-01 2001-06-18 Takeda Chemical Industries Ltd Compuestos de amina ciclica, su produccion y su uso
AU2018301A (en) 1999-12-28 2001-07-24 Pfizer Products Inc. Non-peptidyl inhibitors of vla-4 dependent cell binding useful in treating inflammatory, autoimmune, and respiratory diseases
WO2001055121A1 (en) 2000-01-28 2001-08-02 Kaken Pharmaceutical Co., Ltd. Azepine derivatives
US6143776A (en) 2000-02-02 2000-11-07 Sunesis Pharmaceuticals, Inc. Tosylproline analogs as thymidylate synthase inhibitors
US6511980B2 (en) 2000-05-05 2003-01-28 Ortho Mcneil Pharmaceutical, Inc. Substituted diamine derivatives useful as motilin antagonists
EP1193268A1 (de) 2000-09-27 2002-04-03 Applied Research Systems ARS Holding N.V. Pharmazeutisch aktive Sulfonamidderivate mit sowohl lipophilen als auch ionisierbaren Gruppen als Inhibitoren von Protein-JunKinasen
WO2002051410A2 (en) 2000-12-22 2002-07-04 Akzo Nobel N.V. Phenylthiazole and thiazoline derivatives and their use as antiparasitics
DE60115501T2 (de) 2000-12-27 2006-07-13 Dainippon Sumitomo Pharma Co., Ltd. Neue Carbapenemverbindungen, Arzneimittel und antibakterielles Mittel, das diese enthält, und deren Verwendungen
AU2002248418A1 (en) 2001-02-09 2002-08-28 Massachusetts Institute Of Technology Methods of identifying agents that mediate polypeptide aggregation
US6650463B2 (en) 2001-03-13 2003-11-18 Seiko Epson Corporation Electrophoretic display device
KR100713137B1 (ko) 2001-06-28 2007-05-02 동화약품공업주식회사 신규의 2,4-디플루오로벤즈아미드 유도체
WO2003007955A2 (en) 2001-07-20 2003-01-30 Cancer Research Technology Limited Biphenyl apurinic/apyrimidinic site endonuclease inhibitors to treat cancer
DE10136043A1 (de) 2001-07-25 2003-02-13 Degussa Verfahren zur Herstellung von modifiziertem Ruß
US6956035B2 (en) 2001-08-31 2005-10-18 Inotek Pharmaceuticals Corporation Isoquinoline derivatives and methods of use thereof
EP1448560B1 (de) 2001-11-20 2005-06-15 Eli Lilly And Company 3-substituierte oxindol beta 3 agonisten
SE0201635D0 (sv) 2002-05-30 2002-05-30 Astrazeneca Ab Novel compounds
CN1658849A (zh) 2002-06-05 2005-08-24 株式会社医药分子设计研究所 Ap－1和nfat活化抑制剂
EP1531815B1 (de) 2002-06-27 2014-09-24 Novo Nordisk A/S Glukokinase-aktivatoren
RU2340605C2 (ru) 2002-06-27 2008-12-10 Ново Нордиск А/С Арилкарбонильные производные в качестве терапевтических средств
WO2004011427A2 (en) 2002-07-31 2004-02-05 Smithkline Beecham Corporation Substituted benzanilides as modulators of the ccr5 receptor
WO2004010943A2 (en) 2002-07-31 2004-02-05 Smithkline Beecham Corporation Substituted benzanilides as modulators of the ccr5 receptor
US7186735B2 (en) 2002-08-07 2007-03-06 Sanofi-Aventis Deutschland Gmbh Acylated arylcycloalkylamines and their use as pharmaceuticals
US7338956B2 (en) 2002-08-07 2008-03-04 Sanofi-Aventis Deutschland Gmbh Acylamino-substituted heteroaromatic compounds and their use as pharmaceuticals
JP4399862B2 (ja) 2002-08-09 2010-01-20 味の素株式会社 腸疾患および内臓痛の治療薬
US20040110802A1 (en) 2002-08-23 2004-06-10 Atli Thorarensen Antibacterial benzoic acid derivatives
CN1694704A (zh) 2002-09-06 2005-11-09 詹森药业有限公司 （1h－苯并咪唑－2－基）－（哌嗪基）－甲酮衍生物及其相关化合物作为组胺h4受体拮抗剂用于治疗炎性和过敏性疾病
SE0202838D0 (sv) 2002-09-24 2002-09-24 Astrazeneca Ab Chemical compounds
US7378525B2 (en) 2002-12-23 2008-05-27 Millennium Pharmaceuticals, Inc. CCR8 inhibitors
US7320989B2 (en) 2003-02-28 2008-01-22 Encysive Pharmaceuticals, Inc. Pyridine, pyrimidine, quinoline, quinazoline, and naphthalene urotensin-II receptor antagonists
US7595322B2 (en) 2003-03-27 2009-09-29 Cytokinetics, Inc. Heterocyclic sulfonamides as modulators of cardiac sarcomeres
WO2004099192A2 (en) 2003-04-30 2004-11-18 The Institutes Of Pharmaceutical Discovery, Llc Heterocycle substituted carboxylic acids as inhibitors of protein tyrosine phosphatase-1b
EP1620094A4 (de) 2003-05-06 2010-04-28 Glaxosmithkline Llc Neue chemische verbindungen
US7368457B2 (en) 2003-05-13 2008-05-06 Schering Corporation Bridged N-arylsulfonylpiperidines as gamma-secretase inhibitors
WO2005007621A2 (en) 2003-05-30 2005-01-27 Rigel Pharmaceuticals, Inc. Ubiquitin ligase inhibitors
US20110275630A1 (en) 2003-06-02 2011-11-10 Abbott Laboratories Isoindolinone kinase inhibitors
EP1631559A4 (de) 2003-06-06 2008-08-27 Smithkline Beecham Corp Il-8-rezeptorantagonisten
AR045047A1 (es) 2003-07-11 2005-10-12 Arena Pharm Inc Derivados arilo y heteroarilo trisustituidos como moduladores del metabolismo y de la profilaxis y tratamiento de desordenes relacionados con los mismos
GB0319151D0 (en) 2003-08-14 2003-09-17 Glaxo Group Ltd Novel compounds
US8084457B2 (en) 2003-09-15 2011-12-27 Lead Discovery Center Gmbh Pharmaceutically active 4,6-disubstituted aminopyrimidine derivatives as modulators of protein kinases
GB0325956D0 (en) 2003-11-06 2003-12-10 Addex Pharmaceuticals Sa Novel compounds
US7498050B2 (en) 2003-12-15 2009-03-03 Kraft Foods Global Brands Llc Edible spread composition and packaged product
DE102004009238A1 (de) 2004-02-26 2005-09-08 Merck Patent Gmbh Arylamid-Derivate
WO2005087217A1 (en) 2004-03-05 2005-09-22 The General Hospital Corporation Compositions and methods for modulating interaction between polypeptides
WO2005105785A2 (en) 2004-05-04 2005-11-10 Novo Nordisk A/S Indole derivatives for treatment of obesity
US20090105218A1 (en) 2004-05-29 2009-04-23 7Tm Pharma A/S CRTH2 Receptor Ligands For Therapeutic Use
WO2006002133A1 (en) 2004-06-22 2006-01-05 Schering Corporation Cannabinoid receptor ligands
SG155188A1 (en) 2004-07-30 2009-09-30 Exelixis Inc Pyrrole derivatives as pharmaceutical agents
AU2005278959A1 (en) 2004-08-31 2006-03-09 Astrazeneca Ab Quinazolinone derivatives and their use as B-Raf inhibitors
DE102004042441A1 (de) 2004-08-31 2006-04-06 Sanofi-Aventis Deutschland Gmbh Mit Aminosäuren substituierte Hexahydro-pyrazino(1,2-a)pyrimidin-4,7-dionderivate, Verfahren zu ihrer Herstellung und ihre Verwendung als Arzneimittel
TW200626559A (en) 2004-10-13 2006-08-01 Wyeth Corp Anilino-pyrimidine analogs
WO2006049835A2 (en) 2004-10-19 2006-05-11 Novartis Vaccines And Diagnostics Inc. Indole and benzimidazole derivatives
TW200628463A (en) 2004-11-10 2006-08-16 Synta Pharmaceuticals Corp Heteroaryl compounds
US20060122236A1 (en) 2004-12-06 2006-06-08 Wood Michael R Substituted biaryl-carboxylate derivatives
AR053992A1 (es) 2004-12-22 2007-05-30 Astrazeneca Ab Compuestos quimicos con actividad anticancerosa, un procedimiento para su preparacion, su uso en la preparacion de medicamentos y composicion farmaceutica.
EP1831198B1 (de) 2004-12-22 2009-04-08 AstraZeneca AB Pyridincarbonsäureamidderivate zur verwendung als antikrebsmittel
FI117653B (fi) 2005-02-21 2006-12-29 Eigenor Oy Menetelmä ja laitteisto liikkuvien kohteiden havaitsemiseksi tutkalla
GB0510141D0 (en) 2005-05-18 2005-06-22 Addex Pharmaceuticals Sa Novel compounds B3
WO2006128129A2 (en) 2005-05-26 2006-11-30 Synta Pharmaceuticals Corp. Method for treating cancer
US20070032493A1 (en) 2005-05-26 2007-02-08 Synta Pharmaceuticals Corp. Method for treating B cell regulated autoimmune disorders
US7790726B2 (en) 2005-08-16 2010-09-07 Chemocentryx, Inc. Monocyclic and bicyclic compounds and methods of use
AU2006290442B2 (en) 2005-09-16 2010-07-29 Arrow Therapeutics Limited Biphenyl derivatives and their use in treating hepatitis C
AU2006326494A1 (en) 2005-12-12 2007-06-21 Genelabs Technologies, Inc. N-(6-membered aromatic ring)-amido anti-viral compounds
AU2006331770A1 (en) 2005-12-21 2007-07-05 Schering Corporation Treatment of nonalcoholic fatty liver disease using cholesterol lowering agents and H3 receptor antagonist/inverse agonist
US20090018118A1 (en) 2005-12-29 2009-01-15 Uros Urleb Heterocyclic compounds
EP2019830A4 (de) 2006-05-04 2011-01-19 Inst Hepatitis & Virus Res Hemmer der sekretion von hepatitis-b-virus-antigenen zur behandlung eines chronischen hepatitis-virus
US20080021063A1 (en) 2006-07-18 2008-01-24 Kazantsev Aleksey G Compositions and methods for modulating sirtuin activity
US8153803B2 (en) 2006-07-18 2012-04-10 The General Hospital Corporation Compositions and methods for modulating sirtuin activity
FR2903985B1 (fr) 2006-07-24 2008-09-05 Sanofi Aventis Sa Derives de n-(amino-heteroaryl)-1h-indole-2-carboxamides, leur preparation et leur application en therapeutique
FR2904316B1 (fr) 2006-07-31 2008-09-05 Sanofi Aventis Sa Derives de n-(amino-heteroaryl)-1h-indole-2-carboxamides, leur preparation et leur application en therapeutique.
WO2008022171A1 (en) 2006-08-17 2008-02-21 Boehringer Ingelheim International Gmbh Methods of using aryl sulfonyl compounds effective as soluble epoxide hydrolase inhibitors
WO2008054605A2 (en) 2006-10-06 2008-05-08 Merck & Co., Inc. Non-nucleoside reverse transcriptase inhibitors
WO2008076270A2 (en) 2006-12-13 2008-06-26 Temple University-Of The Commonwealth System Of Higher Education Sulfide, sulfoxide and sulfone chalcone analogues, derivatives thereof and therapeutic uses thereof
US20100022517A1 (en) 2006-12-18 2010-01-28 Richards Lori A Ophthalmic formulation of rho kinase inhibitor compound
US8071779B2 (en) 2006-12-18 2011-12-06 Inspire Pharmaceuticals, Inc. Cytoskeletal active rho kinase inhibitor compounds, composition and use
FR2910473B1 (fr) 2006-12-26 2009-02-13 Sanofi Aventis Sa Derives de n-(amino-heteroaryl)-1h-pyrrolopyridine-2- carboxamides, leur preparation et leur application en therapeutique.
JP2008179621A (ja) 2006-12-28 2008-08-07 Taisho Pharmaceutical Co Ltd 含窒素飽和複素環化合物
JP2008184403A (ja) 2007-01-29 2008-08-14 Japan Health Science Foundation 新規ｃ型肝炎ウイルス阻害剤
AU2008225766B2 (en) 2007-03-15 2012-06-07 Novartis Ag Organic compounds and their uses
US8097728B2 (en) 2007-04-30 2012-01-17 Philadelphia Health & Education Corporation Iminosugar compounds with antiflavirus activity
JP5160637B2 (ja) 2007-05-04 2013-03-13 アイアールエム・リミテッド・ライアビリティ・カンパニー ｃ−ｋｉｔおよびＰＤＧＦＲキナーゼインヒビターとしての化合物および組成物
WO2008154819A1 (fr) 2007-06-18 2008-12-24 Zhang, Zhongneng Thiazolyl-dihydropyrimidines à substitution carbéthoxy
WO2009018219A2 (en) 2007-07-28 2009-02-05 University Of Chicago Methods and compositions for modulating rad51 and homologous recombination
EP2182935A1 (de) 2007-08-02 2010-05-12 F. Hoffmann-Roche AG Verwendung von benzamid-derivaten zur behandlung von leiden des zentralen nervensystems
CN101429166B (zh) 2007-11-07 2013-08-21 上海特化医药科技有限公司 喹唑啉酮衍生物及其制备方法和用途
JP2011507910A (ja) 2007-12-21 2011-03-10 ユニバーシティー オブ ロチェスター 真核生物の寿命を変更するための方法
FR2926556B1 (fr) 2008-01-22 2010-02-19 Sanofi Aventis Derives de carboxamides n-azabicycliques, leur preparation et leur application en therapeutique
FR2926554B1 (fr) 2008-01-22 2010-03-12 Sanofi Aventis Derives de carboxamides azabicycliques, leur preparation et leur application en therapeutique
FR2926555B1 (fr) 2008-01-22 2010-02-19 Sanofi Aventis Derives bicycliques de carboxamides azabicycliques, leur preparation et leur application en therapeutique
FR2926553B1 (fr) 2008-01-23 2010-02-19 Sanofi Aventis Derives d'indole-2-carboxamides et d'azaindole-2- carboxamides substitues par un groupe silanyle, leur preparation et leur application en therapeutique
CU20080028A6 (es) 2008-02-29 2011-02-24 Ct Ingenieria Genetica Biotech Compuestos químicos obtenidos in silico para la preparación de composiciones farmacéuticas para atenuar o inhibir la infección por virus dengue y otros flavivirus
WO2009146013A1 (en) 2008-03-31 2009-12-03 Georgetown University Myosin light chain phosphatase inhibitors
CN102015638A (zh) 2008-04-24 2011-04-13 万有制药株式会社 以芳基磺酰基衍生物作为有效成分的长链脂肪酸延长酶抑制剂
US20090325959A1 (en) 2008-06-26 2009-12-31 Vittitow Jason L Method for treating ophthalmic diseases using rho kinase inhibitor compounds
US8299096B2 (en) 2008-06-26 2012-10-30 Inspire Pharmaceuticals, Inc. Method for treating pulmonary diseases using rho kinase inhibitor compounds
US20090325960A1 (en) 2008-06-26 2009-12-31 Fulcher Emilee H Method for treating inflammatory diseases using rho kinase inhibitor compounds
US8410147B2 (en) 2008-06-26 2013-04-02 Inspire Pharmaceuticals, Inc. Method for treating diseases associated with alterations in cellular integrity using Rho kinase inhibitor compounds
US20100008968A1 (en) 2008-06-26 2010-01-14 Lampe John W Method for treating cardiovascular diseases using rho kinase inhibitor compounds
US8207195B2 (en) 2008-06-26 2012-06-26 Inspire Pharmaceuticals, Inc. Method for treating neurological and neuropathic diseases using rho kinase inhibitor compounds
CA2735392A1 (en) 2008-08-15 2010-02-18 F. Hoffmann-La Roche Ag Bi-aryl aminotetralines
US9040488B2 (en) 2008-09-02 2015-05-26 Baruch S. Blumberg Institute Imino sugar derivatives demonstrate potent antiviral activity and reduced toxicity
US8143269B2 (en) 2008-10-03 2012-03-27 Calcimedica, Inc. Inhibitors of store operated calcium release
WO2010043592A1 (en) 2008-10-15 2010-04-22 Revotar Biopharmaceuticals Ag Lipase inhibitors for use for the treatment of obesity
WO2010059658A1 (en) 2008-11-20 2010-05-27 Glaxosmithkline Llc Chemical compounds
EP2400969A4 (de) 2008-12-04 2012-05-16 Inspire Pharmaceuticals Inc Verfahren zur behandlung von lungenerkrankungen mit rho-kinasehemmerverbindungen
CA2748174A1 (en) 2008-12-30 2010-07-08 Arqule, Inc. Substituted 1h-pyrazolo[3,4-d]pyrimidine-6-amine compounds
WO2010088000A2 (en) 2009-02-02 2010-08-05 Angion Biomedica Corp. Antifibrotic compounds and uses thereof
WO2010123139A1 (ja) 2009-04-24 2010-10-28 持田製薬株式会社 スルファモイル基を有するアリールカルボキサミド誘導体
WO2010133336A1 (en) 2009-05-19 2010-11-25 Bayer Cropscience Ag Insecticidal arylpyrrolines
CN102480957A (zh) 2009-05-27 2012-05-30 Ptc医疗公司 治疗癌症及非肿瘤病症的方法
CN102469788A (zh) 2009-06-30 2012-05-23 西佳技术公司 登革病毒感染的治疗和预防
CA2689707A1 (en) 2009-11-16 2011-05-16 Jean-Simon Diallo Identification of the novel small molecule viral sensitizer vse1 using high-throughput screening
US8822700B2 (en) 2009-09-11 2014-09-02 Enanta Pharmaceuticals, Inc. Hepatitis C virus inhibitors
US8703938B2 (en) 2009-09-11 2014-04-22 Enanta Pharmaceuticals, Inc. Hepatitis C virus inhibitors
WO2011035143A2 (en) 2009-09-17 2011-03-24 The Regents Of The University Of Michigan Methods and compositions for inhibiting rho-mediated diseases and conditions
WO2011058766A1 (en) 2009-11-16 2011-05-19 Raqualia Pharma Inc. Aryl carboxamide derivatives as ttx-s blockers
CN102093320B (zh) 2009-12-09 2013-08-28 扬子江药业集团上海海尼药业有限公司 一种可溶性环氧化物水解酶抑制剂
WO2011088015A1 (en) 2010-01-15 2011-07-21 Boehringer Ingelheim International Gmbh Compounds which modulate the cb2 receptor
WO2011088561A1 (en) 2010-01-20 2011-07-28 University Of Manitoba Anti-viral compounds and compositions
WO2011109237A2 (en) 2010-03-02 2011-09-09 Emory University Uses of noscapine and derivatives in subjects diagnosed with fap
JP2013522192A (ja) 2010-03-11 2013-06-13 ブリストル−マイヤーズ スクイブ カンパニー Ｃ型肝炎の処置のための化合物
CN102206172B (zh) 2010-03-30 2015-02-25 中国医学科学院医药生物技术研究所 一组取代双芳基化合物及其制备方法和抗病毒应用
JP2013523766A (ja) 2010-03-31 2013-06-17 グラクソ グループ リミテッド キナーゼ阻害剤としてのイミダゾリル‐イミダゾール
PH12012502194A1 (en) 2010-05-07 2014-09-05 Glaxosmithkline Llc Indoles
WO2011155898A1 (en) 2010-06-11 2011-12-15 Wadell Goeran New antiviral compounds
US20130142827A1 (en) 2010-06-25 2013-06-06 Philadelphia Health & Education Corporation D/B/A Induction of immune response
WO2012012282A1 (en) 2010-07-19 2012-01-26 Inspire Pharmaceuticals, Inc. Bifunctional rho kinase inhibitor compounds, composition and use
JP2013536178A (ja) 2010-07-26 2013-09-19 ニューロセラピューティクス ファーマ， インコーポレイテッド アリールスルホンアミド誘導体、組成物、および使用方法
BR112013001015A2 (pt) 2010-07-27 2016-05-24 Inspire Pharmaceuticals Inc método por tratar doenças oftálmicas que usam compostos de inibidor de cinase em formas de prodrug
WO2012016133A2 (en) 2010-07-29 2012-02-02 President And Fellows Of Harvard College Ros1 kinase inhibitors for the treatment of glioblastoma and other p53-deficient cancers
WO2012033956A1 (en) 2010-09-08 2012-03-15 Mithridion, Inc. Cognition enhancing compounds and compositions, methods of making, and methods of treating
WO2012047856A2 (en) 2010-10-04 2012-04-12 Institute For Hepatitis And Virus Research Novel inhibitors of secretion of hepatitis b virus antigens
GB201017345D0 (en) 2010-10-14 2010-11-24 Proximagen Ltd Receptor antagonists
EP2646439B1 (de) 2010-12-02 2016-05-25 Bristol-Myers Squibb Company Neue alkylamide als hiv-bindungsinhibitoren
WO2012080050A1 (en) 2010-12-14 2012-06-21 F. Hoffmann-La Roche Ag Solid forms of a phenoxybenzenesulfonyl compound
GB201103419D0 (de) 2011-02-28 2011-04-13 Univ Aberdeen
PH12013502033A1 (en) 2011-04-08 2014-01-06 Janssen Sciences Ireland Uc Pyrimidine derivatives for the treatment of viral infections
US8889716B2 (en) 2011-05-10 2014-11-18 Chdi Foundation, Inc. Transglutaminase TG2 inhibitors, pharmaceutical compositions, and methods of use thereof
EP2726459B1 (de) 2011-07-01 2019-09-11 Baruch S. Blumberg Institute Sulfamoylbenzamidderivate als antivirale mittel gegen hbv-infektionen
CN106957282B (zh) 2011-12-21 2019-08-30 诺维拉治疗公司 B型肝炎抗病毒剂
ES2581489T3 (es) 2012-01-06 2016-09-06 Janssen Sciences Ireland Uc 1,4-dihidropirimidinas 4,4-disustituidas y el uso de las mismas como medicamentos para el tratamiento de la hepatitis B
JP6134338B2 (ja) 2012-02-29 2017-05-24 バルーク エス．ブルームバーグ インスティテュート Ｂ型肝炎ウイルス共有結合閉環状ｄｎａ形成の阻害剤およびそれらの使用方法
US20130267517A1 (en) 2012-03-31 2013-10-10 Hoffmann-La Roche Inc. Novel 4-methyl-dihydropyrimidines for the treatment and prophylaxis of hepatitis b virus infection
CA2865259A1 (en) 2012-03-31 2013-10-03 F. Hoffmann-La Roche Ag Novel 4-methyl-dihydropyrimidines for the treatment and prophylaxis of hepatitis b virus infection
PL2861611T3 (pl) 2012-05-25 2017-08-31 Janssen Sciences Ireland Uc Nukleozydy uracylowe spirooksetanu
WO2013181584A2 (en) 2012-06-01 2013-12-05 Guo, Ju-Tao Modulation of hepatitis b virus cccdna transcription
JO3300B1 (ar) 2012-06-06 2018-09-16 Novartis Ag مركبات وتركيبات لتعديل نشاط egfr
TW201408652A (zh) 2012-07-11 2014-03-01 Hoffmann La Roche 作爲ＲＯＲｃ調節劑之芳基磺內醯胺衍生物
AR092270A1 (es) 2012-08-28 2015-04-08 Janssen R&D Ireland Sulfamoilarilamidas y su uso como medicamentos para el tratamiento de la hepatitis b
UA115069C2 (uk) 2012-08-28 2017-09-11 ЯНССЕН САЙЄНСІЗ АЙРЛЕНД ЮСі Конденсовані біциклічні похідні сульфамоїлу та їх застосування як лікарських препаратів для лікування гепатиту b
EP2892893B2 (de) 2012-09-10 2019-10-16 F.Hoffmann-La Roche Ag 6-aminosäure-heteroaryldihydropyrimidine zur behandlung und prophylaxe der hepatitis-b-virusinfektion
SG11201504740UA (en) 2012-12-27 2015-07-30 Univ Drexel Novel antiviral agents against hbv infection
BR112015020545A2 (pt) 2013-02-28 2017-07-18 Eisai R&D Man Co Ltd derivado de tetraidroimidazo[1,5-d][1,4]oxazepina
ES2628953T3 (es) 2013-02-28 2017-08-04 Janssen Sciences Ireland Uc Sulfamoilarilamidas y el uso de las mismas como medicamentos para el tratamiento de la hepatitis B
WO2014165128A2 (en) 2013-03-12 2014-10-09 Novira Therapeutics, Inc. Hepatitis b antiviral agents
US9944658B2 (en) 2013-03-14 2018-04-17 VenatoRx Pharmaceuticals, Inc. Beta-lactamase inhibitors
MX353412B (es) 2013-04-03 2018-01-10 Janssen Sciences Ireland Uc Derivados de n-fenil-carboxamida y su uso como medicamentos para el tratamiento de la hepatitis b.
MX2015015692A (es) 2013-05-17 2016-03-04 Hoffmann La Roche Novedosas heteroarildihidropirimidinas, unidas por puentes en 6 para el tratamiento y la profilaxis de infeccion por el virus de hepatitis b.
JP6441315B2 (ja) 2013-05-17 2018-12-19 ヤンセン・サイエンシズ・アイルランド・ユーシー スルファモイルチオフェンアミド誘導体およびｂ型肝炎を治療するための医薬品としてのその使用
JO3603B1 (ar) 2013-05-17 2020-07-05 Janssen Sciences Ireland Uc مشتقات سلفامويل بيرولاميد واستخدامها كادوية لمعالجة التهاب الكبد نوع بي
US9688681B2 (en) 2013-05-28 2017-06-27 Bayer Cropscience Aktiengesellschaft Heterocyclic compounds as pest control agents
LT3004090T (lt) 2013-05-28 2018-01-10 Astrazeneca Ab Cheminiai junginiai
WO2014198880A1 (en) 2013-06-14 2014-12-18 Ferrer Internacional, S.A. 2-(2-aminophenoxy)-3-chloronaphthalene-1,4-dione compounds having orexin 2 receptor agonist activity
PL3024819T3 (pl) 2013-07-25 2018-08-31 Janssen Sciences Ireland Uc Pochodne piroloamidowe podstawione glioksamidem i ich zastosowanie jako leków do leczenia wirusowego zapalenia wątroby typu B
WO2015055764A1 (en) 2013-10-18 2015-04-23 Syngenta Participations Ag 3-methanimidamid-pyridine derivatives as fungicides
WO2015057945A1 (en) 2013-10-18 2015-04-23 Indiana University Research And Technology Corporation Hepatitis b viral assembly effectors
SG11201602748XA (en) 2013-10-23 2016-05-30 Janssen Sciences Ireland Uc Carboxamide derivatives and the use thereof as medicaments for the treatment of hepatitis b
US9115113B2 (en) 2013-11-14 2015-08-25 Novira Therapeutics, Inc. Azepane derivatives and methods of treating hepatitis B infections
JO3466B1 (ar) 2013-12-20 2020-07-05 Takeda Pharmaceuticals Co مواد ضابطة لتترا هيدرو بيريدوبيرازينات من gpr6
US9169212B2 (en) 2014-01-16 2015-10-27 Novira Therapeutics, Inc. Azepane derivatives and methods of treating hepatitis B infections
US9181288B2 (en) 2014-01-16 2015-11-10 Novira Therapeutics, Inc. Azepane derivatives and methods of treating hepatitis B infections
DK3099296T3 (en) 2014-01-31 2019-04-15 Cognition Therapeutics Inc ISO-INDOLINE DERIVATIVES, COMPOSITIONS AND METHODS FOR TREATING NEURODEGENERATIVE DISEASE
KR20160128305A (ko) 2014-02-05 2016-11-07 노비라 테라퓨틱스, 인코포레이티드 Hbv 감염의 치료를 위한 병용 요법
ES2705401T3 (es) 2014-02-06 2019-03-25 Janssen Sciences Ireland Uc Derivados de sulfamoilpirrolamida y su uso como medicamentos para el tratamiento de la Hepatitis B
HUE041734T2 (hu) 2014-03-07 2019-05-28 Hoffmann La Roche Új, 6-tagú gyûrûvel kondenzált heteroarildihidropirimidinek hepatitisz B vírusfertõzés kezelésére és megelõzésére
PT3116316T (pt) 2014-03-13 2019-09-30 Assembly Biosciences Inc Moduladores alostéricos da proteína do núcleo da hepatite b
US9400280B2 (en) 2014-03-27 2016-07-26 Novira Therapeutics, Inc. Piperidine derivatives and methods of treating hepatitis B infections
KR20160133563A (ko) 2014-03-28 2016-11-22 선샤인 레이크 파르마 컴퍼니 리미티드 다이하이드로피리미딘 화합물 및 이의 약제학적 용도
CA2950807C (en) 2014-05-30 2022-05-31 Medshine Discovery Inc. Dihydropyrimido fused ring derivative as hbv inhibitor
WO2016089990A1 (en) 2014-12-02 2016-06-09 Novira Therapeutics, Inc. Sulfide alkyl and pyridyl reverse sulfonamide compounds for hbv treatment
US9550779B2 (en) 2014-12-30 2017-01-24 Novira Therapeutics, Inc. Derivatives and methods of treating hepatitis B infections
MA41338B1 (fr) 2015-01-16 2019-07-31 Hoffmann La Roche Composés de pyrazine pour le traitement de maladies infectieuses
EP3271019A1 (de) 2015-03-19 2018-01-24 Novira Therapeutics Inc. Azocan- und azonanderivate und verfahren zur behandlung von hepatitis-b-infektionen
WO2016161268A1 (en) 2015-04-01 2016-10-06 Enanta Pharmaceuticals, Inc. Hepatitis b antviral agents
US10273228B2 (en) 2015-04-17 2019-04-30 Indiana University Research And Technology Corporation Hepatitis B viral assembly effectors
US10738035B2 (en) 2015-05-13 2020-08-11 Enanta Pharmaceuticals, Inc. Hepatitis B antiviral agents
US10875876B2 (en) 2015-07-02 2020-12-29 Janssen Sciences Ireland Uc Cyclized sulfamoylarylamide derivatives and the use thereof as medicaments for the treatment of hepatitis B
JP6845231B2 (ja) 2015-09-29 2021-03-17 ノヴィラ・セラピューティクス・インコーポレイテッド Ｂ型肝炎抗ウイルス薬の結晶形態
KR20180129943A (ko) 2016-04-15 2018-12-05 노비라 테라퓨틱스, 인코포레이티드 캡시드 조립 억제제를 포함하는 배합물 및 방법
CN109251212A (zh) 2017-07-14 2019-01-22 上海长森药业有限公司 内环硫醚酰胺-芳基酰胺类化合物及其治疗乙型肝炎的用途
EP3765011A1 (de) 2018-03-14 2021-01-20 Janssen Sciences Ireland Unlimited Company Dosierungsschema für kapsid-assemblierungsmodulator

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US20200352925A1 (en) 2020-11-12
US11491148B2 (en) 2022-11-08
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AR119732A1 (es) 2022-01-05
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